MDC1 interacts with TOPBP1 to maintain chromosomal stability during mitosis

Leimbacher, Pia-Amata, Jones, Samuel E, Shorrocks, Ann-Marie K, de Marco Zompit, Mara, Day, Matthew, Blaauwendraad, Jordy, Bundschuh, Diana, Bonham, Sarah, Fischer, Roman, Fink, Daniel, Kessler, Benedikt M, Oliver, Antony W, Pearl, Laurence H, Blackford, Andrew N and Stucki, Manuel (2019) MDC1 interacts with TOPBP1 to maintain chromosomal stability during mitosis. Molecular Cell. ISSN 1097-2765

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Abstract

In mitosis, cells inactivate DNA double-strand break (DSB) repair pathways to preserve genome stability. However, some early signaling events still occur, such as recruitment of the scaffold protein MDC1 to phosphorylated histone H2AX at DSBs. Yet, it remains unclear whether these events are important for maintaining genome stability during mitosis. Here, we identify a highly conserved protein-interaction surface in MDC1 that is phosphorylated by CK2 and recognized by the DNA-damage response mediator protein TOPBP1. Disruption of MDC1-TOPBP1 binding causes a specific loss of TOPBP1 recruitment to DSBs in mitotic but not interphase cells, accompanied by mitotic radiosensitivity, increased micronuclei, and chromosomal instability. Mechanistically, we find that TOPBP1 forms filamentous structures capable of bridging MDC1 foci in mitosis, indicating that MDC1-TOPBP1 complexes tether DSBs until repair is reactivated in the following G1 phase. Thus, we reveal an important, hitherto-unnoticed cooperation between MDC1 and TOPBP1 in maintaining genome stability during cell division.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > Q Science (General)
Depositing User: Antony Oliver
Date Deposited: 09 Apr 2019 07:44
Last Modified: 09 Apr 2019 07:45
URI: http://sro.sussex.ac.uk/id/eprint/83083

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Project NameSussex Project NumberFunderFunder Ref
Structural Biology of DNA Damage Response and Repair MechanismsUnsetCANCER RESEARCH UKC302/A24386
Structural Biology of DNA Damage Response and Repair Mechanisms and its Exploitation for Drug DiscovG0891CANCER RESEARCH UKUnset